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1.
Cell Mol Life Sci ; 79(2): 94, 2022 Jan 25.
Article in English | MEDLINE | ID: covidwho-1653404

ABSTRACT

Numerous post-translational modifications (PTMs) govern the collective metabolism of a cell through altering the structure and functions of proteins. The action of the most prevalent PTMs, encompassing phosphorylation, methylation, acylations, ubiquitination and glycosylation is well documented. A less explored protein PTM, conversion of peptidylarginine to citrulline, is the subject of this review. The process of citrullination is catalysed by peptidylarginine deiminases (PADs), a family of conserved enzymes expressed in a variety of human tissues. Accumulating evidence suggest that citrullination plays a significant role in regulating cellular metabolism and gene expression by affecting a multitude of pathways and modulating the chromatin status. Here, we will discuss the biochemical nature of arginine citrullination, the enzymatic machinery behind it and also provide information on the pathological consequences of citrullination in the development of inflammatory diseases (rheumatoid arthritis, multiple sclerosis, psoriasis, systemic lupus erythematosus, periodontitis and COVID-19), cancer and thromboembolism. Finally, developments on inhibitors against protein citrullination and recent clinical trials providing a promising therapeutic approach to inflammatory disease by targeting citrullination are discussed.


Subject(s)
Autoimmune Diseases/pathology , Citrullination/physiology , Inflammation/pathology , Protein Processing, Post-Translational/physiology , Protein-Arginine Deiminases/metabolism , COVID-19/pathology , Citrulline/biosynthesis , Energy Metabolism/physiology , Extracellular Traps/immunology , Gene Expression Regulation/genetics , Humans , Neoplasms/pathology , SARS-CoV-2/immunology , Thromboembolism/pathology
3.
Int J Mol Sci ; 22(20)2021 Oct 18.
Article in English | MEDLINE | ID: covidwho-1470895

ABSTRACT

Innate and adaptive immune responses have a well-known link and represent the distinctive origins of several diseases, many of which may be the consequence of the loss of balance between these two responses. Indeed, autoinflammation and autoimmunity represent the two extremes of a continuous spectrum of pathologic conditions with numerous overlaps in different pathologies. A common characteristic of these dysregulations is represented by hyperinflammation, which is an exaggerated response of the immune system, especially involving white blood cells, macrophages, and inflammasome activation with the hyperproduction of cytokines in response to various triggering stimuli. Moreover, hyperinflammation is of great interest, as it is one of the main manifestations of COVID-19 infection, and the cytokine storm and its most important components are the targets of the pharmacological treatments used to combat COVID-19 damage. In this context, the purpose of our review is to provide a focus on the pathogenesis of autoinflammation and, in particular, of hyperinflammation in order to generate insights for the identification of new therapeutic targets and strategies.


Subject(s)
Adaptive Immunity , Autoimmune Diseases/pathology , Cytokine Release Syndrome/pathology , Immunity, Innate , Autoimmune Diseases/immunology , COVID-19/complications , COVID-19/pathology , COVID-19/virology , Cytokine Release Syndrome/etiology , Cytokine Release Syndrome/immunology , Cytokines/metabolism , Humans , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , SARS-CoV-2/isolation & purification
4.
Front Immunol ; 12: 722979, 2021.
Article in English | MEDLINE | ID: covidwho-1399139

ABSTRACT

The immunopathology of type I diabetes (T1D) presents a complicated case in part because of the multifactorial origin of this disease. Typically, T1D is thought to occur as a result of autoimmunity toward islets of Langerhans, resulting in the destruction of insulin-producing cells (ß cells) and thus lifelong reliance on exogenous insulin. However, that explanation obscures much of the underlying mechanism, and the actual precipitating events along with the associated actors (latent viral infection, diverse immune cell types and their roles) are not completely understood. Notably, there is a malfunctioning in the regulation of cytotoxic CD8+ T cells that target endocrine cells through antigen-mediated attack. Further examination has revealed the likelihood of an imbalance in distinct subpopulations of tolerogenic and cytotoxic natural killer (NK) cells that may be the catalyst of adaptive immune system malfunction. The contributions of components outside the immune system, including environmental factors such as chronic viral infection also need more consideration, and much of the recent literature investigating the origins of this disease have focused on these factors. In this review, the details of the immunopathology of T1D regarding NK cell disfunction is discussed, along with how those mechanisms stand within the context of general autoimmune disorders. Finally, the rarer cases of latent autoimmune, COVID-19 (viral), and immune checkpoint inhibitor (ICI) induced diabetes are discussed as their exceptional pathology offers insight into the evolution of the disease as a whole.


Subject(s)
Autoimmune Diseases/immunology , Diabetes Mellitus, Type 1/immunology , Diabetes Mellitus, Type 1/pathology , Killer Cells, Natural/immunology , Killer Cells, Natural/pathology , Autoantibodies/immunology , Autoimmune Diseases/pathology , COVID-19/complications , Diabetes Mellitus, Type 1/etiology , Humans , Insulin/metabolism , Insulin-Secreting Cells/immunology , Virus Diseases/complications
5.
Int J Mol Sci ; 22(2)2021 Jan 08.
Article in English | MEDLINE | ID: covidwho-1389386

ABSTRACT

Neutrophils are primary effector cells of innate immunity and fight infection by phagocytosis and degranulation. Activated neutrophils also release neutrophil extracellular traps (NETs) in response to a variety of stimuli. These NETs are net-like complexes composed of cell-free DNA, histones and neutrophil granule proteins. Besides the evolutionarily conserved mechanism to capture and eliminate pathogens, NETs are also associated with pathophysiological processes of various diseases. Here, we elucidate the mechanisms of NET formation and their different implications in disease. We focused on autoinflammatory and cardiovascular disorders as the leading cause of death. Neutrophil extracellular traps are not only present in various cardiovascular diseases but play an essential role in atherosclerotic plaque formation, arterial and venous thrombosis, as well as in the development and progression of abdominal aortic aneurysms. Furthermore, NETosis can be considered as a source of autoantigens and maintains an inflammatory milieu promoting autoimmune diseases. Indeed, there is further need for research into the balance between NET induction, inhibition, and degradation in order to pharmacologically target NETs and their compounds without impairing the patient's immune defense. This review may be of interest to both basic scientists and clinicians to stimulate translational research and innovative clinical approaches.


Subject(s)
Autoimmune Diseases/immunology , Extracellular Traps/immunology , Neutrophils/immunology , Aortic Aneurysm, Abdominal/pathology , Autoimmune Diseases/pathology , Autoimmunity/immunology , COVID-19/immunology , COVID-19/pathology , Humans , Neutrophil Activation/immunology , Plaque, Atherosclerotic/pathology , Thrombosis/pathology
6.
Front Immunol ; 12: 624703, 2021.
Article in English | MEDLINE | ID: covidwho-1354863

ABSTRACT

Accumulating evidence suggests that the breakdown of immune tolerance plays an important role in the development of myocarditis triggered by cardiotropic microbial infections. Genetic deletion of immune checkpoint molecules that are crucial for maintaining self-tolerance causes spontaneous myocarditis in mice, and cancer treatment with immune checkpoint inhibitors can induce myocarditis in humans. These results suggest that the loss of immune tolerance results in myocarditis. The tissue microenvironment influences the local immune dysregulation in autoimmunity. Recently, tenascin-C (TN-C) has been found to play a role as a local regulator of inflammation through various molecular mechanisms. TN-C is a nonstructural extracellular matrix glycoprotein expressed in the heart during early embryonic development, as well as during tissue injury or active tissue remodeling, in a spatiotemporally restricted manner. In a mouse model of autoimmune myocarditis, TN-C was detectable before inflammatory cell infiltration and myocytolysis became histologically evident; it was strongly expressed during active inflammation and disappeared with healing. TN-C activates dendritic cells to generate pathogenic autoreactive T cells and forms an important link between innate and acquired immunity.


Subject(s)
Autoimmune Diseases/metabolism , Autoimmunity , Cardiomyopathies/metabolism , Inflammation Mediators/metabolism , Myocarditis/metabolism , Myocardium/metabolism , Tenascin/metabolism , Animals , Autoimmune Diseases/immunology , Autoimmune Diseases/pathology , Cardiomyopathies/immunology , Cardiomyopathies/pathology , Cellular Microenvironment , Humans , Myocarditis/immunology , Myocarditis/pathology , Myocardium/immunology , Myocardium/pathology , Self Tolerance , Signal Transduction
7.
BMJ Case Rep ; 14(5)2021 May 24.
Article in English | MEDLINE | ID: covidwho-1242196

ABSTRACT

IgG4-related disease (IgG4-RD) is a systemic fibroinflammatory disease characterised by dense lymphoplasmacytic infiltration rich in IgG4-positive plasma cells, storiform fibrosis and obliterative phlebitis. Serum IgG4 levels are typically elevated but half of the patients had normal serum IgG4 levels. IgG4-RD represents a spectrum of diseases that involve various organs such as the pancreas, liver, kidneys, and salivary glands often manifesting as diffuse organ enlargement or a mass-like lesion mimicking cancer. An increased incidence of malignancy among patients with IgG4-RD has been reported. Thus, differentiating malignancy from IgG4-RD manifestation is important as the treatment differs. Glucocorticoids are considered first-line therapy and should be started early to prevent fibrosis. Patients usually have an excellent clinical response to steroids, and poor steroid response is indicative of an alternative diagnoses such as malignancy. This case report describes a case of IgG4-RD with renal mass in a young man that resolved with glucocorticoid therapy alone.


Subject(s)
Autoimmune Diseases , Phlebitis , Autoimmune Diseases/diagnosis , Autoimmune Diseases/drug therapy , Autoimmune Diseases/pathology , Fibrosis , Humans , Immunoglobulin G , Male , Plasma Cells/pathology , Steroids
8.
Front Immunol ; 12: 672808, 2021.
Article in English | MEDLINE | ID: covidwho-1236674

ABSTRACT

The anti-inflammatory role of extra-adrenal glucocorticoid (GC) synthesis at epithelial barriers is of increasing interest with regard to the search for alternatives to synthetic corticosteroids in the therapy of inflammatory disorders. Despite being very effective in many situations the use of synthetic corticosteroids is often controversial, as exemplified in the treatment of influenza patients and only recently in the current COVID-19 pandemic. Exploring the regulatory capacity of locally produced GCs in balancing immune responses in barrier tissues and in pathogenic disorders that lead to symptoms in multiple organs, could provide new perspectives for drug development. Intestine, skin and lung represent the first contact zones between potentially harmful pathogens or substances and the body, and are therefore important sites of immunoregulatory mechanisms. Here, we review the role of locally produced GCs in the regulation of type 2 immune responses, like asthma, atopic dermatitis and ulcerative colitis, as well as type 1 and type 3 infectious, inflammatory and autoimmune diseases, like influenza infection, psoriasis and Crohn's disease. In particular, we focus on the role of locally produced GCs in the interorgan communication, referred to as gut-skin axis, gut-lung axis or lung-skin axis, all of which are interconnected in the pathogenic crosstalk atopic march.


Subject(s)
Glucocorticoids/immunology , Intestinal Mucosa/immunology , Lung/immunology , Skin/immunology , Anti-Inflammatory Agents , Autoimmune Diseases/immunology , Autoimmune Diseases/pathology , Dermatitis, Atopic/immunology , Dermatitis, Atopic/pathology , Epithelium/immunology , Glucocorticoids/biosynthesis , Humans , Inflammation , Intestinal Mucosa/pathology , Lung/pathology , Skin/pathology
9.
ESC Heart Fail ; 8(1): 756-760, 2021 02.
Article in English | MEDLINE | ID: covidwho-938416

ABSTRACT

We report a unique case of a young woman with recurrent immune-mediated (virus-negative) lymphocytic fulminant myocarditis during the coronavirus disease 2019 pandemic. At the first endomyocardial biopsy (EMB)-proven episode, she had concomitant pneumonia, and a temporary biventricular assist device implant was followed by complete and long-lasting cardiac recovery. Five years later, she was re-admitted for relapsing cardiogenic shock with a recent history of pneumonia. She was treated with extracorporeal life support with apical venting for left ventricular unloading, and full recovery was achieved. Despite negative seriate nasopharyngeal swabs and EMB during hospitalization, an antibody positivity for severe acute respiratory syndrome coronavirus 2 was discovered after 4 weeks from discharge. This is the first report of an EMB-proven, immune-mediated (virus-negative) recurrence of fulminant myocarditis. We hypothesize that in patients with a predisposing immunogenetic background, autoimmune disease may be triggered or reactivated by major infections, for example, pneumonia, that may act as adjuvants leading to an immune-mediated hyper-response.


Subject(s)
Autoimmune Diseases/etiology , COVID-19/complications , Myocarditis/etiology , Adult , Autoimmune Diseases/pathology , Autoimmune Diseases/physiopathology , Biopsy , Electrocardiography , Female , Humans , Myocarditis/pathology , Myocarditis/physiopathology , Myocardium/pathology , Recurrence
10.
Int J Mol Sci ; 21(9)2020 May 08.
Article in English | MEDLINE | ID: covidwho-209974

ABSTRACT

On 7 January 2020, researchers isolated and sequenced in China from patients with severe pneumonitis a novel coronavirus, then called SARS-CoV-2, which rapidly spread worldwide, becoming a global health emergency. Typical manifestations consist of flu-like symptoms such as fever, cough, fatigue, and dyspnea. However, in about 20% of patients, the infection progresses to severe interstitial pneumonia and can induce an uncontrolled host-immune response, leading to a life-threatening condition called cytokine release syndrome (CRS). CRS represents an emergency scenario of a frequent challenge, which is the complex and interwoven link between infections and autoimmunity. Indeed, treatment of CRS involves the use of both antivirals to control the underlying infection and immunosuppressive agents to dampen the aberrant pro-inflammatory response of the host. Several trials, evaluating the safety and effectiveness of immunosuppressants commonly used in rheumatic diseases, are ongoing in patients with COVID-19 and CRS, some of which are achieving promising results. However, such a use should follow a multidisciplinary approach, be accompanied by close monitoring, be tailored to patient's clinical and serological features, and be initiated at the right time to reach the best results. Autoimmune patients receiving immunosuppressants could be prone to SARS-CoV-2 infections; however, suspension of the ongoing therapy is contraindicated to avoid disease flares and a consequent increase in the infection risk.


Subject(s)
Antiviral Agents/therapeutic use , Coronavirus Infections/drug therapy , Coronavirus Infections/immunology , Cytokine Release Syndrome/pathology , Pneumonia, Viral/drug therapy , Pneumonia, Viral/immunology , Autoimmune Diseases/complications , Autoimmune Diseases/drug therapy , Autoimmune Diseases/pathology , Betacoronavirus/physiology , COVID-19 , Clinical Trials as Topic , Coronavirus Infections/complications , Coronavirus Infections/pathology , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/immunology , Humans , Immunosuppressive Agents/therapeutic use , Pandemics , Pneumonia, Viral/complications , Pneumonia, Viral/pathology , SARS-CoV-2
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